Diabetes Ther (2016) 7:621–639 DOI 10.1007/s13300-016-0208-5
REVIEW
Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the Disease Joel Zonszein . Per-Henrik Groop
Received: August 19, 2016 / Published online: October 31, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
ABSTRACT
effectively as first-line therapy in combination with metformin, as well as in patients not
Introduction: The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely
achieving therapy.
impact small and large vessels, eventually
Methods: For this review, a non-systematic
leading to microvascular and macrovascular complications. Failure of therapeutic lifestyle
literature search of PubMed, NCBI, and Google Scholar was conducted.
changes, monotherapy, and clinical inertia contribute to persistent hyperglycemia and
Results: New oral agents have made it possible to improve glycemic control to near-normal
disease progression. The aim was to review the
levels with a low risk of hypoglycemia and
complex pathophysiology of type 2 diabetes and how different oral agents can be used
without weight gain, and sometimes with weight loss. Early combination therapy is
Enhanced Content To view enhanced content for this article go to http://www.medengine.com/Redeem/ 0217F060488512AE. J. Zonszein (&) Montefiore Medical Center, University Hospital for Albert Einstein College of Medicine, Bronx, NY, USA e-mail:
[email protected] glycemic
goals
with
metformin
effective and has been shown to have a favorable legacy effect. A number of agents are available in a single-pill combination (SPC) that provides fewer pills and better adherence. Compared with adding a sulfonylurea, still the most common oral combination used, empagliflozin has been shown to decrease
P.-H. Groop Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
cardiovascular (CV) events in a dedicated CV
P.-H. Groop Folkha¨lsan Institute of Genetics, Folkha¨lsan Research Center, Biomedicum Helsinki, Helsinki, Finland
endpoints, whereas sulfonylureas have been associated with an increased risk of CV disease.
P.-H. Groop Baker IDI Heart & Diabetes Institute, Melbourne, Australia
outcome study, and pioglitazone has been effective in reducing the risk of secondary CV
In those failing metformin, triple oral therapy by adding a non-metformin SPC such as empagliflozin/linagliptin or pioglitazone/
Diabetes Ther (2016) 7:621–639
622
alogliptin is a good option for reducing glycated
periods of time (even years) before adding
hemoglobin (HbA1c) hypoglycemia.
additional therapy [4]. This step-up approach
without
significant
Conclusion: Clinicians have a comprehensive armamentarium of medications to treat patients with T2DM. Clinical evidence has shown that dual or triple oral combination therapy is effective for glycemic control, and early treatment is effective in getting patients to goal more quickly. Use of SPCs is an option for double or triple oral combination therapy and may result in better adherence.
glycemic control is often not durable [5, 6]. Several studies have stressed the importance of early treatment, not only to prevent small vessel disease complications, but to prevent cardiovascular (CV) events years after the completion of the trial (a result of the legacy effect) as well [7–9]. The
Keywords: DPP-4 inhibitors; Early combination therapy; Hyperglycemia; Hypoglycemia; Oral glucose-lowering agents; SGLT2 inhibitors; Single-pill Type 2 diabetes mellitus
is conducive to treatment failure; evidence from monotherapy studies shows that long-term
combination;
current therapeutic landscape also
results from caution based on potential adverse events with available glucose-lowering agents [4]. For example, insulins and sulfonylureas (SUs) are associated with weight gain and hypoglycemia [1], the latter being of particular concern in the elderly [10]. The management of T2DM may be facilitated with
INTRODUCTION
single-pill combinations (SPC) by enabling patients to take fewer pills per day, which may
Over the last several decades, the diabetes
lead to improved patient adherence [11]. Many combinations include metformin and can be
landscape improved
has
been transformed by understanding of
an its
used early in the disease. Two other SPCs,
pathophysiology and the development of an
pioglitazone/alogliptin and empagliflozin/ linagliptin, have shown good glucose-lowering
array of antihyperglycemic medications [1]. Yet, diabetes remains a pervasive disease with
efficacy when added to metformin [12, 13]. It is important to choose agents that treat the
immense public health consequences and increasing prevalence of type 2 diabetes
patient as a whole, not just their hyperglycemia.
mellitus (T2DM) in adults [2]. Despite the
For example, individuals with T2DM are at high risk of CV disease and need aggressive therapy
number of treatment options, hyperglycemia is still often poorly controlled [3], chiefly
that includes the management of concomitant CV risk factors such as obesity, hypertension,
reflecting the limitations inherent in treatment options for T2DM and clinical
and dyslipidemia [14]. In addition, patients
inertia. Lifestyle changes such as diet or
with T2DM and chronic kidney disease (CKD) are also at an increased risk of severe
exercise are insufficient, and the efficacy of pharmacologic agents is rarely sustained over
hypoglycemia [15] and present a treatment challenge. Metformin is not recommended for
time and may be limited by side effects. After prescribing therapeutic lifestyle changes, there
use in patients with an estimated glomerular
may be delays in initiating monotherapy, often
filtration rate (eGFR) less than 45 mL/min/ 1.732; however, metformin may be used safely
metformin, and physicians may wait long
in patients with mild impairment in kidney
Diabetes Ther (2016) 7:621–639
623
function and with proper monitoring in
empagliflozin.
patients with moderate impairment in kidney
identified after screening the titles, and results
function [16]. As the number of newly diagnosed patients with T2DM increases and
were then revised qualitatively on the basis of treatment initiation time and use of
patients live longer, CKD needs to be a consideration when choosing
combination or fixed-dose therapy. Relevant clinical trials evaluating early combination
antihyperglycemic
recently
therapy in patients with T2DM were identified
published long-term follow-up to the Steno-2 trial of patients with T2DM and
on ClinicalTrials.gov. Other sources included drug manufacturers’ websites and references
microalbuminuria, more intensified, multifactorial, target-driven treatment resulted
known to the author.
in an almost 8-year longer survival with fewer
Compliance with Ethics Guidelines
CV complications [17]. Thus, a one-size-fits-all approach to treat hyperglycemia is insufficient
This article is based on previously conducted
and a patient-centered approach is necessary. Herein, we describe the rationale for early
studies and does not involve any new studies of human or animal subjects performed by any of
combination
the authors.
agents.
therapy,
In
review
the
the
clinical
efficacy and safety data for the empagliflozin/ linagliptin SPC, and discuss how SPC therapy can be used in a personalized approach. This review discusses only oral agents as they are more commonly used early in the disease. Of the nine classes of oral medications listed in
Relevant
references
were
PATHOPHYSIOLOGY T2DM is a complex disease with multiple pathophysiologic
components
(Fig. 1).
Table 1, this paper focuses on the newer classes,
Elevated blood glucose results from insufficient insulin production and insulin
dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT-2)
resistance, as well as a closely intertwined dysfunction of many other metabolic and
inhibitors, available in the USA, as well as the older SUs and thiazolidinediones (TZDs), agents
hormonal
that are commonly prescribed when metformin
pathways
[18].
Impaired
b cell
function and impaired insulin secretion are hallmarks of T2DM. In addition, pancreatic
fails.
a cells secrete inappropriately high amounts of glucagon in spite of hyperglycemia and
REVIEW METHODS
hyperinsulinemia, the two major factors that
For this narrative review, a non-systematic
decrease glucagon secretion and endogenous glucose production. As a result, inappropriate
literature search was conducted on various databases, including PubMed, NCBI, and Google Scholar. The search terms included
endogenous glucose production leads to fasting hyperglycemia and also contributes to postprandial hyperglycemia.
type 2 diabetes, early treatment with oral agents such as linagliptin, empagliflozin,
T2DM has evolved into a disorder that now affects a younger population afflicted with
metformin, DPP-4 inhibitors, and fixed-dose combination with linagliptin and
central obesity and abnormal adipocyte function [19]. In addition, the gastrointestinal
Diabetes Ther (2016) 7:621–639
624
Table 1 Classes of oral medications for glycemic management approved in the USA [1, 24] Class
Compounds
Primary physiologic action
Hypoglycemia
Weight
Biguanides
Metformin
; Hepatic glucose production
Neutral
Slight loss
Sulfonylureas
Glyburide/glibenclamide
: Insulin secretion
Moderate/severe Gain
: Insulin secretion
Mild
Gain
: Insulin sensitivity
Neutral
Gain
Slows carbohydrate digestion/absorption
Neutral
Neutral
Neutral
Neutral
Neutral
Neutral
Neutral
Neutral
Glimepiride Glipizide Meglitinides
Repaglinide Nateglinide
Thiazolidinediones
Pioglitazone Rosiglitazone
a-Glucosidase inhibitors
Acarbose
DPP-4 inhibitors
Alogliptin
: Insulin secretion (glucose-dependent)
Linagliptin
; Glucagon secretion (glucose-dependent)
Miglitol
Sitagliptin Saxagliptin Bile acid sequestrants
Colesevelam
Dopamine-2 agonists
Bromocriptine (quick release)
; Hepatic glucose production (?) : Incretin levels (?) Modulates hypothalamic regulation of metabolism : Insulin sensitivity
SGLT2 inhibitors
Canagliflozin
Inhibit glucose reabsorption by the kidney Neutral
Dapagliflozin
: Glucosuria
Loss
Empagliflozin DPP-4 dipeptidyl peptidase-4, SGLT2 sodium glucose cotransporter 2
tract exhibits abnormal secretion of incretin
during fasting, and reabsorbing all of the
hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide
filtered glucose [21], both of which are adaptive mechanisms that ensure sufficient
[18, 20]. These two hormones account for 90%
energy is available during fasting periods. The
of the incretin effect, which plays a pivotal role in maintaining normal glucose homeostasis.
transport protein, SGLT2, is a low-affinity, high-capacity glucose transporter that
The kidneys also play a crucial role in glucose homeostasis by releasing glucose into the
reabsorbs approximately 90% of filtered glucose, while the high-affinity, low-capacity
circulation via gluconeogenesis, particularly
SGLT1 transporter reabsorbs the remainder [22].
Diabetes Ther (2016) 7:621–639
625
Fig. 1 Pathophysiologic abnormalities targeted by currently available antihyperglycemic medications. DPP4i dipeptidyl peptidase 4 inhibitor, GLP1 RA glucagon-like peptide 1 receptor agonist, HGP hepatic glucose production, MET metformin, SGLT2i sodium glucose cotransporter 2 inhibitor, TZD thiazolidinedione. ‘ From the
triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus’’. American Diabetes Association, 2009. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association
A maladaptation takes place in individuals with diabetes with increased expression and activity
glucose dysregulation. In summary, complex and multiple pathophysiologic disturbances
of SGLT2 in the proximal tubule of the kidney.
involving different organs and endocrine and
As a result, glucose reabsorption increases by as much as 20% in individuals with poorly
neurologic pathways cause hyperglycemia, and therefore it is not surprising that a multitiered
controlled diabetes, contributing to hyperglycemia [22]. In T2DM and obesity, the
treatment approach is necessary.
central nervous system fuel feedback is affected
TREATMENT GUIDELINES AND APPROACHES
by insulin and leptin resistance, further contributing to glycemic dysregulation. Individuals with obesity and T2DM are insulin and leptin resistant and display neurotransmitter dysfunction that alters the normal fuel feedback to the brain [23], making the central nervous system a critical player in
Treatment
guidelines
developed
by
the
American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), as well as by the American Association of Clinical Endocrinologists (AACE) and the
Diabetes Ther (2016) 7:621–639
626
American College of Endocrinology (ACE), recommend
metformin
as
the
pharmacotherapy if lifestyle changes, such as diet and exercise, fail to achieve glycated hemoglobin (HbA1c) goals within 3 months [1, 24]. Metformin does not cause significant hypoglycemia, is weight neutral, inexpensive, and has a long-standing evidence base for efficacy and safety [1]; it may even reduce the risk of CV events [7]. On the basis of the Diabetes Prevention Program study, metformin is also recommended for individuals with prediabetes, particularly those with a body mass index greater than 35 kg/m2, aged less than 60 years, and women with previous gestational diabetes [25, 26]. If metformin is contraindicated (e.g., because of decreased renal function) or not tolerated, the AACE/ACE guidelines suggest the use of one of the newer agents, such as a GLP-1 receptor agonist, SGLT2 inhibitor, or DPP-4 inhibitor, over older agents (a-glucosidase inhibitors, TZDs, and SUs) [24]. The ADA/EASD Position Statement does not prioritize treatments and instead emphasizes patient preference and individualized treatment [1]. Individuals with T2DM benefit from learning adopting
DPP-4 Inhibitors
first-choice
about managing their disease, a healthier lifestyle, and
understanding the pros and cons of their medications. Well-structured education, such as diabetes self-management education, should
DPP-4 inhibitors are gastrointestinal peptides that enhance secretion of insulin from pancreatic b cells and suppress glucagon release from pancreatic a cells glucose-dependent manner [29].
in a DPP-4
inhibitors have a low risk of hypoglycemia, are weight neutral, have been shown to improve b cell function in animal and in vitro studies [30, 31], and can exert several favorable effects on the CV system, including improved ventricular
function
[32].
Currently,
four
DPP-4 inhibitors are approved in the USA for the treatment of hyperglycemia alone or in combination with other oral agents and insulin: alogliptin, linagliptin, sitagliptin, and saxagliptin (Table 2). In clinical trials, DPP-4 inhibitor monotherapy has been shown to improve glycemic control with mean reductions in HbA1c in the range of 0.6–1.1% [33]. When used in patients with moderate or severe
CKD,
alogliptin,
saxagliptin,
and
sitagliptin require a lower dose [34]. Linagliptin, the only DPP-4 inhibitor primarily excreted via the hepatic route, does not require any dose adjustment. All DPP-4 inhibitors are well tolerated, but have been associated with an increased frequency of stuffy nose or cough [35] and some cases of severe and disabling arthralgia have been reported more recently [36]. Reports of pancreatitis and pancreatic
aim to support informed decision-making, problem-solving, and active collaboration with
cancer with the use of incretinomimetics are
the health care team to improve clinical
still under investigation [37].
outcomes, health status, and quality of life in a cost-effective manner [27, 28]. Monitoring
SGLT2 Inhibitors
glycemic goals via determination of HbA1c levels and self-monitoring of blood glucose (SMBG) varies according to the individual and
SGLT2 inhibitors exert their effects via the kidney and their mechanism of action
his or her treatment [1].
involves inhibiting the SGLT2 protein in the
2.5/1000 XR–5/1000 XR 2.5/1000 XR–5/500 XR–5/1000 XR
JentaduetoÒ XR (Boehringer Ingelheim Pharmaceuticals, Inc.) KombiglyzeÒ XR (AstraZeneca Pharmaceuticals, LP)
Linagliptin ? metformin XR
Saxagliptin ? metformin XR
DPP-4 inhibitor ? TZD
Combinations without metformin
Glyburide ? metformin
SU ? metformin Generic
2.5/500–5/500
Twice daily
Twice daily
2/500–4/500–2/10–4/1000
AvandametÒ (GlaxoSmithKline)
Rosiglitazone ? metformin
Twice daily Once daily
15/500–15/850
Actoplus Met XR (Takeda Pharmaceuticals America, Inc.) 15/1000–30/1000
Ò
Actoplus MetÒ (Takeda Pharmaceuticals America, Inc.)
Pioglitazone ? metformin XR
Pioglitazone ? metformin
TZD ? metformin
5/500 –5/1000 – 12.5/500 – 12.5/1000
SynjardyÒ (Boehringer Ingelheim Pharmaceuticals, Inc.)
Empagliflozin ? metformin
Twice daily
5/500 XR–5/1000 XR–10/500 XR–10/1000 Once daily XR
XigduoÒ XR (AstraZeneca Pharmaceuticals, LP)
Dapagliflozin ? metformin XR
Twice daily
50/500 XR–50/1000 XR–150/500 XR–150/ Once daily 1000 XR
50/500–50/1000–150/500–150/1000
Invokamet XR (Janssen Pharmaceuticals, Inc.)
Ò
Once daily
Twice daily
Once daily
Once daily
Twice daily
Twice daily
Administration
Canagliflozin ? metformin XR
Canagliflozin ? metformin
InvokametÒ (Janssen Pharmaceuticals, Inc.)
50/500 XR–50/1000 XR–100/1000 XR
JanumetÒ XR (Merck Sharp & Dohme Corp.)
Sitagliptin ? metformin XR
SGLT2 inhibitor ? metformin
50/500–50/1000
Janumet (Merck Sharp & Dohme Corp.)
Sitagliptin ? metformin
Ò
2.5/500–2.5/850–2.5/1000
12.5/500–12.5/1000
Jentadueto (Boehringer Ingelheim Pharmaceuticals, Inc.)
Ò
KazanoÒ (Takeda Pharmaceuticals America, Inc.)
Dosages, mg/mg
Linagliptin ? metformin
Alogliptin ? metformin
DPP-4 inhibitor ? metformin
Combinations with metformin
Brand name
Table 2 SPC therapies available for T2DM in the USA
Diabetes Ther (2016) 7:621–639 627
Diabetes Ther (2016) 7:621–639
Please consult full prescribing information for contraindications, warnings and precautions, and dosage and administration for use in specific populations (e.g., renal impairment) DPP-4 dipeptidyl peptidase 4, SGLT2 sodium glucose cotransporter 2, SU sulfonylurea, T2DM type 2 diabetes mellitus, TZD thiazolidinedione, XR extended release
Once daily 4/1–4/2–4/4–8/2–8/4 Generic Rosiglitazone ? glimepiride
Once daily Pioglitazone ? glimepiride
TZD ? SU
DuetactÒ (Takeda Pharmaceuticals America, Inc.)
GlyxambiÒ (Boehringer Ingelheim Pharmaceuticals, Inc.) Empagliflozin ? linagliptin
SGLT2 inhibitor ? DPP-4 inhibitor
10/5–25/5
30/2–30/4
Once daily
Once daily 12.5/15–12.5/30–12.5/45–25/15–25/ 30–25/45 OseniÒ (Takeda Pharmaceuticals America, Inc.) Alogliptin ? pioglitazone
Table 2 continued
Brand name
Dosages, mg/mg
Administration
628
proximal
nephron,
thereby
reducing
the
inappropriately increased glucose reabsorption found in T2DM and increasing urinary glucose excretion [38]. SGLT2 inhibitors have proven to be effective not only in improving glycemic management but also in decreasing weight and reducing systolic blood pressure (BP), with a low risk of hypoglycemia, except when used with insulin or SUs [38]. They provide significant reductions in HbA1c versus placebo and are similarly efficacious when compared with most standard oral agents in head-to-head trials [39]. Because this action is independent of insulin, SGLT2 inhibitors may be used at any stage of T2DM, even after insulin secretion has waned significantly [38]. The SGLT2 inhibitors lead to increased risk of genital mycotic infections, particularly in women. Urinary tract infections have also been reported to be more common in some patient groups, such as older patients, but the increase is less clear-cut than for genital infections [40]. Use of SGLT2 inhibitors also has the potential to cause hypotension and other hypovolemic events because of osmotic diuresis, particularly in older patients taking loop diuretics. In addition, trials have shown small increases in low-density lipoprotein cholesterol
and,
although
these
can
be
managed with appropriate treatment, the long-term consequences are unclear. Long-term trials to establish CV safety are still ongoing for canagliflozin and dapagliflozin
[41].
Results
from
the
Ò
EMPA-REG OUTCOME trial showed a significant CV risk reduction [42], decreased CV and overall mortality, slower progression of kidney disease, and lower rates of clinically relevant renal events in patients with T2DM and CV risk factors who were treated with empagliflozin versus placebo in addition to standard of care [43] (see ‘‘CV Risk’’ section).
Diabetes Ther (2016) 7:621–639
629
Post-marketing reports of ketoacidosis have
Cardiovascular Outcomes and Regulation of
emerged after the approval of SGLT2 inhibitors,
Glycaemia in Diabetes (RECORD), compared
with a number of cases reporting minimal elevation of blood sugar (i.e., euglycemic
metformin plus SU with metformin plus rosiglitazone, and also found better glycemic
ketoacidosis) [44]. The US Food and Drug Administration (FDA) has subsequently issued
control with the combination of rosiglitazone and metformin [48]. Since these are the only
a warning alerting health care practitioners and
two
patients to the ketoacidosis [45].
available, treatment decisions should be patient-centered and include considerations
signs
and
symptoms
of
long-term
randomized
clinical
trials
such as efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and
Combination Therapy
patient preferences [25]. Current guidelines recommend combination therapy in patients with elevated HbA1c levels
Although many shorter-term trials have compared dual therapy versus metformin
at diagnosis (ADA/EASD[9.0%; AACE/ ACE C7.5%) or after 3 months of monotherapy
monotherapy, few long-term, head-to-head studies have directly compared drugs as
if HbA1c goals are not achieved [1, 24]. To address the lack of long-term studies assessing
add-on therapy. A comparative effectiveness
the efficacy and safety of initial combination
meta-analysis suggests that, overall, each new class of non-insulin agents added to initial
therapy, the US National Institutes of Health has sponsored the Glycemia Reduction
therapy lowers HbA1c levels by approximately 1% [49]. These differences may be true in
Approaches in Diabetes: A Comparative Effectiveness (GRADE) study [46]. The trial
clinical trials, however, in day-to-day practice tremendous variability occurs among patients’
does not compare older combinations, such as TZDs, or newer agents, such as the SGLT2
responses to medications.
inhibitors, and is limited to comparing the combination of metformin with DPP-4 inhibitors, GLP-1 receptor agonists, insulin, or
CV RISK
SUs. Until the GRADE trial is completed (estimated 2020), only two randomized,
Intensive Glucose Lowering
controlled, long-term studies (both 5 years) are
CV disease is the major cause of morbidity and premature mortality and an important
available. First, Revascularization
the Bypass Investigation
Angioplasty 2 Diabetes
contributor to the direct and indirect costs of
different (mainly
diabetes [50]. Benefits can be seen when multiple risk factors (e.g., BP, weight, smoking cessation)
insulin and SUs) versus insulin sensitizers
are addressed globally [51, 52]. Long-term clinical trials have also shown that aggressive glycemic
(BARI 2D) study compared two strategies, insulin secretagogues
(mainly metformin and rosiglitazone). The study showed that the insulin sensitizer
treatment benefits CV outcomes years after the
strategy not only achieved better glycemic control but was also associated with less
studies have been completed [7–9, 52]. These effects have been clearly demonstrated in patients
hypoglycemia and less weight gain [47]. The
with type 1 diabetes mellitus (T1DM) in the Diabetes Control and Complications Trial/
second
trial,
Rosiglitazone
Evaluated
for
Diabetes Ther (2016) 7:621–639
630
Epidemiology of Diabetes Interventions and
Several CV outcomes trials have compared
Complications study (DCCT/EDIC) [53]. This
DPP-4 inhibitors with placebo or other agents in
was also shown in patients with T2DM in the UK Prospective Diabetes Study (UKPDS) [7], and more
addition to the usual standard of care for glycemic control and CV risk factors [62–64].
recently in the long-term follow-up of the Veterans Affairs Diabetes Trial (VADT) in which
In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes
CV disease improvement was found 10 years after
Mellitus–Thrombolysis in Myocardial Infarction
the study end [8], the legacy effect [7]. Although the Action to Control Cardiovascular Risk in
(SAVOR-TIMI) 53 trial, which compared saxagliptin versus placebo in T2DM patients
Diabetes (ACCORD) study found that intensive therapy (targeting HbA1c\6.0%) in patients with
with either a history of established CV events or at high risk of CV events (N = 16,492) over a
T2DM
with
median of 2.1 years, the rates of the composite
standard therapy (targeting HbA1c 7.0–7.9%) [54], the VADT and the Action in Diabetes and
primary endpoint [CV death, nonfatal myocardial infarction (MI), or ischemic stroke]
Vascular Disease (ADVANCE) trials showed that intensive glucose control did not increase
were similar between the treatment groups [hazard ratio (HR), 1.00; 95% confidence
mortality [55, 56]. VADT showed a reduction in
interval
CV event rates years after the study was completed (median follow-up, 5.6 years) [8]. However,
non-inferiority; P = 0.99 for superiority] [62]. However, saxagliptin showed a higher rate of
interventions at a later disease stage, such as intensive treatment in those with heart and
hospitalization due to heart failure (3.5%) relative to placebo (2.8%; HR, 1.27; 95% CI,
kidney disease, can also produce a legacy effect after aggressive multifactorial treatment
1.07–1.51; P = 0.007) [62]. In the Examination of Cardiovascular Outcomes with Alogliptin
initiation. A recent follow-up to the Steno-2
versus Standard of Care (EXAMINE) trial,
trial, following patients for a mean of 21.2 years after 7.8 years of intensified multifactorial
which investigated alogliptin versus placebo in patients with acute coronary syndrome over a
treatment in patients with T2DM and microalbuminuria, demonstrated a median gain
median of 1.5 years, alogliptin was non-inferior to placebo for the primary composite endpoint
of 7.9 life-years [17].
(CV death, nonfatal MI, or nonfatal stroke): HR,
When metformin is not indicated or tolerated, including in treatment-naı¨ve
0.96; upper boundary of the one-sided repeated CI, 1.16; P\0.001 for non-inferiority; P = 0.32
individuals, the empagliflozin/linagliptin SPC can be a good alternative. Although the
for superiority [63]. Moreover, in a post hoc analysis, the first hospitalization due to heart
addition of an SU is the most common step
failure occurred at similar rates in both
after metformin fails, these agents have been associated with hypoglycemia, sometimes
treatment groups (alogliptin, 3.1%, placebo, 2.9%; HR, 1.07; 95% CI, 0.79–1.46; P = 0.657)
requiring hospitalizations, particularly in the elderly [10] and in those with polypharmacy
[64]. The larger (N = 14,671) and longer (median follow-up, 3.0 years) Trial Evaluating
increased
mortality
compared
(CI),
0.89–1.12;
P\0.001
for
[57]. Observational cohort trials have also
Cardiovascular
shown a disadvantage of SUs in general [58, 59], and when compared to DPP-4
(TECOS) trial evaluated sitagliptin versus placebo on top of usual care in patients at
inhibitors [60, 61].
least 50 years of age with T2DM and established
Outcomes
with
Sitagliptin
Diabetes Ther (2016) 7:621–639
631
reassuringly
heart failure (HR, 0.65; 95% CI, 0.50–0.85;
demonstrated no increased risk versus placebo
P = 0.002), and death from any cause (HR,
for the primary composite CV endpoint of CV death, nonfatal MI, nonfatal stroke, or
0.68; 95% CI, 0.57–0.82; P\0.001). Among patients receiving empagliflozin, there was an
hospitalization for unstable angina (alogliptin, 9.6%, placebo, 9.6%; HR, 0.98; 95% CI,
increased rate of genital infection but no increase in other adverse events.
CV
disease
[65].
The
results
0.88–1.09; P\0.001 for non-inferiority in the per-protocol population; P = 0.65 for superiority) and no increase in hospitalization
CV Outcomes Trials with TZDs
for heart failure [HR in the intent-to-treat analysis: 1.00 (95% CI, 0.83–1.20); P = 0.98]
The TZDs are among the most potent insulin-sensitizing drugs available. Their use in
[65].
patients with T2DM has decreased mainly as a result of the adverse CV outcomes attributed to
CV Outcomes Trials with SGLT2 Inhibitors
rosiglitazone [68]. Pioglitazone, the other agent
Ongoing clinical trials assessing the impact of
in this class, may reduce the risk of CV events, including stroke [69]. The PROspective
the SGLT2 inhibitors dapagliflozin and canagliflozin in patients with T2DM at high
PioglitAzone Clinical Trial In macro-Vascular Events (PROactive) trial evaluated the addition
risk of CV complications include Dapagliflozin
of pioglitazone to current therapy in patients
Effect on CardiovascuLAR Events (DECLARE-TIMI 58) [41] and CANagliflozin
with T2DM and a history of macrovascular disease (N = 5238). Although the trial failed to
cardioVascular Assessment Study (CANVAS) [66, 67]. For empagliflozin, the recently
meet its primary composite endpoint of death from any cause, nonfatal MI, stroke, acute
completed EMPA-REG OUTCOMEÒ trial is the first dedicated CV outcome study to demonstrate
coronary syndrome, leg amputation, coronary revascularization, or revascularization of the
that a glucose-lowering agent can improve CV
leg, a significant reduction in the composite
endpoints and lower CV mortality as well as all-cause mortality in patients with T2DM at
secondary endpoint was observed (death from any cause, nonfatal MI, or nonfatal stroke: HR
high risk of CV events [42]. It evaluated the effects of empagliflozin (10 or 25 mg once daily
0.84; 95% CI, 0.72–0.98; P = 0.027) [70]. In a follow-up analysis, the pioglitazone reduced
versus placebo) on top of standard of care on CV
rates of fatal or nonfatal stroke and the
outcomes in 7020 patients with T2DM at high risk of CV disease. The primary outcome was a
composite of CV death, nonfatal stroke, or MI among patients with a history of previous stroke
composite of death from CV causes, nonfatal MI, or nonfatal stroke (3-point major adverse
[69]. More recently, pioglitazone was also found to lower the risk of stroke or MI in individuals
cardiovascular
was
without diabetes who had insulin resistance
significantly reduced with empagliflozin (HR, 0.86, 95% CI, 0.74–0.99; P\0.001 for
along with ischemic stroke or transient ischemic attacks [71]. Although pioglitazone
non-inferiority and P = 0.04 for superiority). Empagliflozin resulted in significantly lower
has shown beneficial CV outcomes, other studies with the long-term use of TZDs,
rates of death from CV causes (HR, 0.62; 95%
mainly rosiglitazone [48, 72], have shown no
CI, 0.49–0.77; P\0.001), hospitalization for
superiority.
events
or
MACE)
and
Diabetes Ther (2016) 7:621–639
632
SPC THERAPY
antihyperglycemic SPCs are easy to tolerate, easy to prescribe, require little or no dose
Individuals with T2DM are often exposed to polypharmacy, not only because of the need for multiple antihyperglycemic agents but also because of additional medications for the treatment of hypertension,
CV risk factors, including dyslipidemia, and other
comorbidities [73]. In the Diabetes and Aging Study, which analyzed data from more than 46,000 patients with T2DM in the USA, the mean number of prescribed medications was 4.2, with 14% of patients taking more than seven medications [74]. Similarly large numbers of medications were used by patients in the UKPDS 35 prospective observational study and the BARI 2D trials [47, 75]. Given the substantial polypharmacy, strategies to improve adherence are welcome in T2DM. As such, treatment with an SPC can facilitate medication adherence,
titration, are associated with a low risk of hypoglycemia, and therefore need less frequent blood glucose monitoring. Efficacy is generally comparable between SPCs and separate-pill combination therapy [84]. Although randomized controlled studies of SPCs are limited, most studies demonstrate improved or equivalent efficacy of the SPCs compared with the monotherapies [83]. Pharmacokinetic studies have demonstrated bioequivalence for several SPCs with their corresponding loose-pill regimens, including those with metformin extended release (XR) [e.g., Actoplus MetÒ XR (Takeda Pharmaceuticals America, Inc.), KombiglyzeÒ XR (AstraZeneca Pharmaceuticals, LP), and JanumetÒ XR (Merck Sharp & Dohme Corp.)]
with the goal of improving health outcomes.
[83]. Metformin, the most commonly found agent in the SPC therapies currently available in
Using SPCs simplifies the treatment regimen by decreasing the number of pills and reducing
the USA, is effective in reducing blood glucose levels, but some patients have difficulty
the frequency of administration. Studies show that adherence is improved with administration
tolerating
this
agent
because
of
adverse
of one tablet per day versus multiple tablets per
gastrointestinal effects [85]. Despite these adverse effects, metformin remains the most
day [76–81]. Greater improvements in glycemic control have also been shown with an SPC
commonly prescribed medication, both in monotherapy and combination [86]. SPCs are
versus the same medications coadministered as separate pills [77]. However, data directly
particularly useful when they can be taken once
addressing the effects of antihyperglycemic
daily, and there are many fixed-dose combinations containing metformin XR
SPCs with respect to health care costs are quite limited [82]. Some data suggest reduced health
(Table 2), which also improves gastrointestinal tolerability [83]. One pill a day facilitates
care utilization and costs with an SPC versus loose-pill regimens [11]—a paradox as many
adherence [76].
formularies penalize SPCs with higher prices.
As with metformin, SUs have also been used extensively in SPC therapies, partly because
Prescribing an SPC limits dose flexibility, and thus many physicians prefer using them as a
they have been available for many years and partly because they are generic and thus
maintenance option rather than an initial therapy. However, the SPCs currently available
relatively inexpensive. The initial SPC was a
for use in T2DM are formulated in a variety of
combination of metformin and an SU. It was followed by an SU combined with a TZD, now
dosage combinations [83] (Table 2). Modern
also available in a generic form (Table 2). These
Diabetes Ther (2016) 7:621–639
633
SPCs may be less frequently prescribed because
24 weeks
they are associated with the disadvantages of
25 mg/linagliptin
was
higher
with
SUs; namely, lack of glycemic durability, hypoglycemia, and weight gain [25]. The third
empagliflozin 10 mg/linagliptin 5 mg (62.3%) versus empagliflozin alone (25 mg, 41.5%;
type of SPC therapy contains neither metformin nor an SU; these agents can be added to
10 mg, 38.8%) or linagliptin alone (5 mg, 32.3%) [88]. In this trial, however, the
metformin when metformin alone is no longer
empagliflozin 25 mg/linagliptin 5 mg SPC was
sufficient. There are only two such SPCs approved by the US FDA: pioglitazone/
not significantly better than empagliflozin 25 mg alone. When compared with linagliptin
alogliptin [OseniÒ (Takeda Pharmaceuticals America, Inc.)] and empagliflozin/linagliptin
5 mg alone, both SPC doses significantly reduced HbA1c, suggesting that without
[GlyxambiÒ
5 mg
empagliflozin (55.4%)
and
Ingelheim
metformin the glucose reduction is mostly
Pharmaceuticals, Inc.)] [87]. The combination of dapagliflozin/saxagliptin was submitted for
driven by empagliflozin [88]. Body weight reductions with the SPCs were also similar to
FDA review, and the FDA has asked for additional data.
empagliflozin alone, as were systolic BP reductions from baseline (2.1–2.5 mmHg) and
(Boehringer
a low incidence of hypoglycemia. Empagliflozin/Linagliptin SPC
In both of these trials, events consistent with urinary tract infections occurred at comparable
When treatment with metformin alone is not sufficient, the empagliflozin/linagliptin SPC can
rates across all groups (10–16%), and events consistent with genital infection were present
provide better HbA1c reductions than empagliflozin or linagliptin alone. In a
in 2–8.5% of patients, mostly women. In summary, the empagliflozin/linagliptin SPC is
placebo-controlled study (n = 674), 61.8% and 57.8% of patients with baseline HbA1c of at
well tolerated, may cause a modest weight loss
least 7.0% achieved an HbA1c of less than 7.0%
with lower systolic BP, and has a low rate of hypoglycemia.
at week 24 with empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 10 mg/linagliptin 5 mg,
Pioglitazone/Alogliptin SPC
respectively, versus 28.0–36.1% of patients who were using any of the three agents alone [13]. Even greater HbA1c reductions were achieved in
Another available SPC is pioglitazone plus alogliptin. In drug-naı¨ve patients, the
individuals with a baseline HbA1c of at least 8.5%, and these improvements in glycemic
combination with pioglitazone 30 mg/ alogliptin 25 mg resulted in greater reductions
control were associated with weight loss and reduced systolic BP [13].
in HbA1c (-1.7 ± 0.1% from an 8.8% mean baseline) versus pioglitazone 30 mg
The empagliflozin/linagliptin SPC may be a
(-1.2 ± 0.1%, P\0.001) or alogliptin 25 mg
good alternative when metformin is not indicated or tolerated or in treatment-naı¨ve individuals. In treatment-naı¨ve patients with
(-1.0 ± 0.1%, P\0.001) alone [89]. When added to metformin, the pioglitazone/
T2DM and moderate hyperglycemia (n = 677;
alogliptin SPC was also well tolerated and effective [12]. When administered to
mean HbA1c, 8.0%), the proportion who
individuals with HbA1c 7.5–10.0% receiving at
achieved HbA1c levels less than 7.0% at
least 1500 mg/day of metformin, pioglitazone
Diabetes Ther (2016) 7:621–639
634
plus metformin (pooled group) achieved a
Several CV outcomes trials have been
mean HbA1c reduction from baseline of 0.9%.
completed for the individual glucose-lowering
In contrast, participants receiving triple therapy (alogliptin, pioglitazone, and metformin)
agents. CV outcomes trials for sitagliptin, saxagliptin, and alogliptin have shown no
achieved a mean HbA1c reduction of 1.4% (P\0.001 versus the pioglitazone plus
increased risk of overall CV events. EMPA-REG OUTCOME is the only trial that has
metformin pooled group).
demonstrated that adding empagliflozin causes a reduction in major adverse CV events, all-cause mortality, CV mortality, and heart
CONCLUSIONS Antihyperglycemic SPCs have been developed in an effort to address the issues of adherence
failure, as well as an improvement in renal outcomes, when compared to treatment placebo on top of the current recommended
associated with combination pharmacotherapy for patients with T2DM, with the goal of
standard of care [42, 43]. In a post hoc analysis pioglitazone has also been found to have
optimizing
favorable CV outcomes when used for secondary intervention when compared to
clinical
outcomes.
Most
SPCs
contain metformin or an SU. On the basis of current guidelines, metformin is the preferred
placebo [69, 70]. In summary, we now have
choice for one of the agents in combination therapy. The use of SUs is less desirable because
different choices in the selection of oral agents available for management of hyperglycemia.
of weight gain, hypoglycemia, and potential CV
While the treatment choice needs to be patient-centered, we now have medications
risks. When considering orally administered alternatives or additions to metformin therapy, agents with a low risk of hypoglycemia that provide weight neutrality or weight loss and have a proven CV safety profile are preferred. In the USA,
two
combinations are alogliptin/pioglitazone and empagliflozin.
Both
non-metformin available, linagliptin/
combinations
contain
DPP-4 inhibitors, which are associated with weight neutrality. However, when used in combination, linagliptin/empagliflozin is associated with weight loss due to the SGLT2 component,
and
alogliptin/pioglitazone
is
associated with weight gain due to the TZD component. These combinations are associated with a low risk of hypoglycemia (except when used in conjunction with insulin or insulin secretagogues). Neither combination has been studied in a dedicated CV outcomes trial.
that in addition to glycemic control also reduce CV outcomes. Early diagnosis of T2DM and aggressive glycemic treatment may help preserve b cell function. In addition, clinical studies suggest that aggressive and early glycemic therapy reduces complications, and the use of lifestyle changes together with initial combination therapy is recommended. Clinicians now have a choice of what to use initially with metformin, or what to add when metformin fails. Newer combinations are weight neutral or may provide weight loss. Adding an SPC may improve adherence by decreasing the number of pills needed. Finally, the cost of expensive newer medications must be measured along with the potential costs of complications associated
with
older
medications.
For
example, sulfonylureas are associated with hypoglycemia, and medical interventions for
Diabetes Ther (2016) 7:621–639
635
hypoglycemia often require more monitoring
Pharmaceuticals North America, Inc, Sanofi,
and sometimes costly hospitalizations [90].
and Boehringer Ingelheim. P-H Per-Henrik Groop has received
In managing diabetes, early diagnosis and treatment with better lifestyles and proper
honoraria
from
AstraZeneca,
Groop lecture
Boehringer
medications can normalize HbA1c without hypoglycemia and/or weight gain. The use of
Ingelheim, Eli Lilly, Genzyme, MSD, Novartis, Novo Nordisk; has received
SPC
investigator-initiated grants from Eli Lilly and Roche; and is a member of advisory boards for
therapy
is
recommended
for
better
adherence, and a more aggressive early treatment should result in fewer complications and a better quality of life. Consideration is needed in every case to provide a
AbbVie, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, MSD, Novartis, and Sanofi.
the
Compliance with Ethics Guidelines. This
patient as a whole. This necessarily includes taking into account concomitant risk factors
article is based on previously conducted studies and does not involve any new studies
such as obesity, hypertension, dyslipidemia, and renal impairment, as well as addressing
of human or animal subjects performed by any
patient-centered
approach
that
treats
of the authors.
medication risk–benefit profiles and costs, when making treatment choices.
Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License
ACKNOWLEDGEMENTS
(http://creativecommons.org/licenses/
No funding or sponsorship was received for this
by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any
study or publication of this article. Editorial support for this manuscript was provided by
medium, provided you give appropriate credit to the original author(s) and the source, provide
Linda Merkel, PhD, of Envision Scientific
a link to the Creative Commons license, and
Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.
indicate if changes were made.
(BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy
as
well
as
intellectual
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